Summary: Mechanisms maintaining the self-awareness of peripheral T cells The ability of T cells in our peripheral immune system to robustly respond when stimulated by their antigen is highly desirable in the context of repelling attacks by dangerous pathogens. In contrast, strong T cell responses to self-antigens would be pathogenic, leading to autoimmune disease. Therefore, as a central tenet of the clonal selection theory, the immune system is expected to eliminate strongly autoreactive T cells during development in the thymus and dampen the remaining self-reactivity by peripheral mechanisms. In this context, it is surprising that all T cells undergo positive selection on self-peptides in the thymus ? ensuring that they are all at least nominally self-reactive. After positive selection a series of TCR-proximal tuning mechanisms, including the upregulation of a cell-surface glycoprotein CD5, ensures that this self-reactivity is not pathogenic. In recent years it is increasingly clear that despite such tuning, peripheral T cells not only continue to be aware of their self-ligands but also use this self-awareness to promote responses to pathogens. The mechanisms of these linked processes are not fully understood. Based on our preliminary studies, we propose that biochemical signals downstream of CD5 itself help to promote the preferential activation and survival of better self-aware T cells in the peripheral Immune system. Here, we propose to use CD5-conditional-knockout mice and infectious challenges to test this hypothesis. The significance of these studies is that it is expected to provide a more comprehensive model for how self-recognition synergizes with pathogen-specific responses in the T cell compartment. The insights gained from these studies can lead to future translational approaches improving the design of vaccines as well as informing the selection and design of T cell transfer therapies.